The present invention relates generally to lipid compositions. More particularly, the present invention relates to lipid compositions comprising a carbohydrate backbone, and to supramolecular structures comprising the same. In a preferred embodiment, the lipid composition further comprises a phospholipid.
A lipid compound, including particularly a phospholipid compound, typically comprises a hydrophilic head group, a lipophilic tail group, a backbone, and linker moieties between the head group and backbone and tail group and backbone, respectively. The most common backbone for a phospholipid, including particularly naturally occurring phospholipids, is a glycerol backbone.
In the art, many different variations of phospholipids have been synthesized by changing linkers, head groups and tail groups. See e.g. U.S. Pat. No. 4,426,330 to Sears; Thomas, B. N.; et al., J. Am. Chem. Soc. 1998, 120, 12178-12186; Srisiri, W.; et al., J. Am. Chem. Soc. 1996, 118, 11327-11328. The glycerol backbone of a phospholipid compound has also been modified. Two major classes of non-glycerol-based synthetic phospholipids exist in the art, the phosphonolipids and the cyclopentane-based phospholipids. See e.g. Engel, R. Chem. Rev. 1977, 77, 349-367; Bittman, R. Chemical Synthesis of glycerophospholipds and their analogs; Bittman, R., Ed.; CRC Press: Boca Raton, Fla., United States of America, 1999, pp 185-207. These modified phospholipids exhibit different physical properties from their glycerol-based analogs, indicating the importance of backbone on bilayer structure. Thus, the preparation and characterization of lipids having modified backbones represents an ongoing need and effort in the art.
Phospholipid structure plays an important role in determining the supramolecular structures formed in solution. Israelachvili, J. N. Intermolecular and Surface Forces; Academic Press Inc.: San Diego, 1992. Specifically, the hydrophilic charged head and hydrophobic tail(s) groups influence the supramolecular and bilayer structure formed, as well as the physical and mechanical properties of these bilayers. For example, the properties of negatively charged phospholipids and their corresponding supramolecular structures can also be dependent upon environmental conditions such as pH and cation concentration. Van Dijck, P. W. M.; et al., Biochim. Biophys. Acta. 1978, 512, 84-96. Bilayer structures formed from anionic phospholipids are also dependent on the chemical constituents of the amphiphilic compound as demonstrated by anionic phospholipids containing a cyclopentane or a dipenta-decylmethylidene backbone instead of glycerol. Ahmad, T. Y.; et al., Chem. Phys. Lipids 1990, 55, 231-243; Blume, A.; Eibl, H. Biochim. Biophys. Acta. 1981, 640, 609-618.
Three conformational changes occur in a bilayer membrane at the critical gel-liquid crystalline phase-transition temperature (Tm): rotational isomers from all-trans to multiple gauche in the tails of the molecule, rapid lateral diffusion within the bilayer membrane, and bilayer area expansion. All three of these factors are important in establishing the phase-transition temperature. For example, electrostatic interactions affect bilayer area. With an increase in phospholipid charge, inter-phospholipid repulsions increase, yielding an increase in bilayer area, and a decrease in Tm. Trauble, H.; Eibl, H. Proc. Nat Acad. Sci. USA 1974, 71, 214-219. Variations in pH are also known to alter the Tm, and this effect is particularly significant in those pH regions similar to the pKa""s of the head group. Sensitivity to the aqueous solution in which the bilayer resides is important physiologically, since changes in pH and ion concentration alter bilayer physical properties. Van Dijck, P. W. M.; et al., J. Biochim. Biophys. Acta. 1978, 512, 84-96. The manipulation of these and other characteristics and variables in a supramolecular structure composition comprising a phospholipid thus represents an ongoing research effort and unsolved problem in the art.
This present invention pertains to a unique class of lipids where the glycerol backbone is replaced with a carbohydrate. In a series of preferred embodiments, zwitterionic, anionic, and cationic carbohydrate-based phospholipids were synthesized and characterized, and novel functionalities were observed. Thus, the present invention meets a long-felt and continuing need in the art for a novel lipid compound, a novel supramolecular structure comprising the same, and for methods of making and using the same.
A lipid compound comprising: 
where each carbon of Cn+1 and C1 to Cn is a stereochemical center; each carbon of C1 to Cn is a member of a heterocyclic ring containing M; n=4, 5, 6 or 7; R1, R2, R3, R4, R5 and R6 are the same or different, and are selected from the group consisting of H, OH, amine, thiol, methoxy, straight or branched chain ester of 6-50 carbon atoms, straight or branched chain silane of 6-50 carbon atoms, straight or branched chain amide of 6-50 carbon atoms, straight or branched chain urea of 6-50 carbon atoms, straight or branched chain urethane of 6-50 carbon atoms, straight or branched chain carbonate of 6-50 carbon atoms, straight or branched chain sulfate of 6-50 carbon atoms, straight or branched chain thiol-urethane of 6-50 carbon atoms, straight or branched chain phosphate of 6-50 carbon atoms, straight or branched chain amine of 6-50 carbon atoms, straight or branched chain thio-urea of 6-50 carbon atoms, straight or branched chain thio-ether of 6-50 carbon atoms, straight or branched chain thio-ester of 6-50 carbon atoms, straight or branched chain ether of 6-50 carbon atoms, and any combination thereof, wherein the chain is fully saturated, fully unsaturated or any combination thereof; M and X1 the same or different and are O, S, or Nxe2x80x94R7, wherein R7 is H, a lower alkane, a chain as recited for R1, R2, R3, Se or any isoelectronic species of oxygen and a=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; X2 is phosphonate, phosphate, boronophosphate, thiophosphate, or selenophosphate and b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; X3=methylene or a monomer selected from the group consisting of an ether, an ester, an amine, acrylic acid, amino acid, a nucleic acid, or a monosaccharide, and c=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20; X4=hydroxide, N-succinyl derivative, a monomer selected from the group consisting of an amine, an ether, an ester, an amino acid, monosaccharide, and a nucleic acid, Nxe2x80x94(R8)e where R8 is hydrogen or methylene chain of 1-20 carbons, or cyclic forms thereof and d=0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and e=1, 2 or 3.
The present invention also provides a novel supramolecular structure comprising a compound of Formula (I). The present invention also provides processes of making and methods of using the novel compounds and compositions.
Accordingly, it is an object of the present invention to provide a novel lipid compound, and a novel supramolecular structure composition comprising the compound. This and other objects are achieved in whole or in part by the present invention.
Some of the objects of the invention having been stated herein above, other objects will become evident as the description proceeds when taken in connection with the accompanying drawings and Laboratory Examples as best described herein below.